1. Field of the Invention
The present invention relates to novel chiral intermediates for taxol side chain, and to a novel process for the preparation of these intermediates.
2. Background Art
Taxol (I) is a natural product that has been shown to display excellent antitumor activity both in vitro and in vivo, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is currently undergoing clinical trials in the United States and France and preliminary results have confirmed it as a most promising chemotherapeutic agent.
The clinical success of taxol has brought forth considerable concern over its supply. Taxol is extracted from the bark of slow-growing yew trees by difficult and low-yielding isolation process, and the need to harvest large number of yew trees has also raised ecological concerns. The observation that a related substance, 10-deacetyl baccatin III (II), is present in large amounts in the leaves of Taxus baccata has led several research teams to devise semisynthetic routes to taxol starting from 10-deacetyl baccatin III. ##STR2##
Denis et al U.S. Pat. No. 4,924,011 discloses the preparation of taxol by reacting 7-triethylsilylbaccatin III and (2R, 3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine followed by removal of the protecting groups. An improved synthesis of chiral 3-phenylisoserine compounds is reported in Denis et al, J. Org. Chem., 1990, 55:1957-1959.
Holton in European Application 400,971 published Dec. 5, 1990 discloses the use of hydroxy protected 1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone as the C-13 side chain of taxol in the acylation of protected baccatin III. The azetidinone is formed by the condensation of an acyloxyacetyl chloride and N-benzylidene-p-methoxy-aniline; however, the product so formed is a racemic mixture which requires resolution to obtain the desired enantiomer. The synthesis of the named azetidinone by the above-described method is also reported by Palomo et al in Tet. Lett., 1990, 31:6529-6432.
Ojima et al in J. Org. Chem., 1991, 56:1681-1683, report the condensation of (silyloxy)acetates bearing a chiral auxiliary with N-(trimethylsilyl)imines to give 3-hydroxy-4-aryl-2-azetidinones in high enantiomeric purity. However, the chiral (silyloxy)acetates are neither commercially available nor inexpensive to prepare requiring enzymatic resolution.
Chiral synthesis of 2-azetidinones is also of importance in other areas of medicinal chemistry, most notably in the .beta.-lactam antibiotic area. Bose et al in J. Org. Chem., 1982, 47:4075-4081 report the condensation of azidoacetyl chloride with a N-(phenylpropenylidene)-D-threonine ester to form the correspondingly substituted cis-2-azetidinone as a 1:1 diastereomeric mixture. Tenneson and Belleau in Can. J. Chem., 1980, 58:1605-1607 report that when the hydroxy group of a N-(phenylpropenylidene)-D-threonine ester is protected with t-butyldimethylsilyl group, the product cis-2-azetidinone is obtained in 9:1 diastereomeric ratio. Wagle et al in J. Org. Chem., 1988, 53:4227-4236 allude to a similar reaction in which triphenylsilyl is used as the hydroxy protecting group to give a 95:5 diastereomeric mixture.
Although the reported cyclocondensation reactions utilizing an imine derived from hydroxy protected D-threonine and azidoacetyl chloride result in high diasteroeselectivity, such favorable outcome cannot be extrapolated to reactants bearing other substituents since this type of reaction is known to be sensitive to the type of substituents used in both reaction partners. For example, Wharton et al in J. Chem. Soc. Perkin Trans. I, 1984, 29-39 reports the cyclocondensation of N-benzylidene-L-Ala-L-Pro t-butyl ester with inter alia phenoxyacetyl chloride or benzyloxyacetyl chloride; however, the product yield was very low, and there was virtually no diastereoselectivity.
In our own experience, we found that reaction of benzyloxyacetyl chloride with N-benzylidene-o-(diphenyl-t-butylsilyl)-(L)-threonine p-nitrobenzyl ester resulted in a 2:1 diastereomeric mixture of the azetidinone; and when t-butyldiphenylsilyloxyacetyl chloride was used, no azetidinone was isolated. Thus it was unexpected that the use of an acyloxyacetyl chloride in the cyclocondensation would result in a better than 10:1 diastereomeric mixture of azetidinones favoring the desired diastereomer.